Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells

Jeffrey Y W Mak, Weijun Xu, Robert C Reid, Alexandra J. Corbett, Bronwyn S. Meehan, Huimeng Wang, Zhenjun Chen, Jamie Rossjohn, James McCluskey, Ligong Liu, David P. Fairlie

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Abstract

Mucosal-associated invariant T (MAIT) cells are activated by unstable antigens formed by reactions of 5-amino-6-D-ribitylaminouracil (a vitamin B2 biosynthetic intermediate) with glycolysis metabolites such as methylglyoxal. Here we show superior preparations of antigens in dimethylsulfoxide, avoiding their rapid decomposition in water (t1/2 1.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC50 3-500 pM), and chemical stabilities are described. Computer analyses of antigen structures reveal stereochemical and energetic influences on MAIT cell activation, enabling design of a water stable synthetic antigen (EC50 2 nM). Like native antigens, this antigen preparation induces MR1 refolding and upregulates surface expression of human MR1, forms MR1 tetramers that detect MAIT cells in human PBMCs, and stimulates cytokine expression (IFNy 3, TNF) by human MAIT cells. These antigens also induce MAIT cell accumulation in mouse lungs after administration with a co-stimulant. These chemical and immunological findings provide new insights into antigen properties and MAIT cell activation.

Original languageEnglish
Article number14599
Number of pages13
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 8 Mar 2017

Keywords

  • antigen processing and presentation
  • chemical tools
  • chemical synthesis
  • T cells

Cite this

Mak, J. Y. W., Xu, W., Reid, R. C., Corbett, A. J., Meehan, B. S., Wang, H., ... Fairlie, D. P. (2017). Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. Nature Communications, 8, [14599]. https://doi.org/10.1038/ncomms14599
Mak, Jeffrey Y W ; Xu, Weijun ; Reid, Robert C ; Corbett, Alexandra J. ; Meehan, Bronwyn S. ; Wang, Huimeng ; Chen, Zhenjun ; Rossjohn, Jamie ; McCluskey, James ; Liu, Ligong ; Fairlie, David P. / Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. In: Nature Communications. 2017 ; Vol. 8.
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Mak, JYW, Xu, W, Reid, RC, Corbett, AJ, Meehan, BS, Wang, H, Chen, Z, Rossjohn, J, McCluskey, J, Liu, L & Fairlie, DP 2017, 'Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells', Nature Communications, vol. 8, 14599. https://doi.org/10.1038/ncomms14599

Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. / Mak, Jeffrey Y W; Xu, Weijun; Reid, Robert C; Corbett, Alexandra J.; Meehan, Bronwyn S.; Wang, Huimeng; Chen, Zhenjun; Rossjohn, Jamie; McCluskey, James; Liu, Ligong; Fairlie, David P.

In: Nature Communications, Vol. 8, 14599, 08.03.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Fairlie, David P.

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